CN106535964B

CN106535964B - pre-filled injection device

Info

Publication number: CN106535964B
Application number: CN201580039578.0A
Authority: CN
Inventors: 埃内斯托·奥罗菲诺
Original assignee: Olo Fino Pharmaceutical Group LLC
Current assignee: Olo Fino Pharmaceutical Group LLC
Priority date: 2014-07-22
Filing date: 2015-06-17
Publication date: 2019-12-10
Anticipated expiration: 2035-06-17
Also published as: EP3171918A1; US20170203047A1; JP2017522115A; ES2675890T3; EP3171918B1; CN106535964A; CA2952845A1; CA2952845C; TR201809101T4; WO2016012878A1; LT3171918T; PL3171918T3; US10363375B2; PT3171918T; JP6689816B2

Abstract

It is described a pre-filled injection device (1) comprising: -a tubular containment body (3) extending between a first opening (4) and a second opening (5), inside which a first containment chamber (8) and a second containment chamber (9) are defined, hermetically separated from each other; -a first solid or liquid substance, contained in a first containment chamber (8); -a first plug (6) and a second plug (7) arranged inside the tubular body (3) so as to define a second housing chamber (9) in the tubular body (3) between them, and adapted to slide inside the tubular body (3); -a second liquid substance, contained within the second containment chamber (9), intended to be mixed with the first substance within the tubular body (3) for reconstituting the injectable solution. The injection device further comprises a dosing container (20) having an inlet opening (21) and an outlet opening (22), the inlet opening (21) communicating with the first receiving chamber (8) such that the first receiving chamber (8) extends between the first plug (6) and the inlet opening (21) of the dosing container (20). The dosing container (20) is adapted to contain a portion of an injectable solution. The first plug (6) comprises a projecting appendix (16) adapted to pass through an inlet opening (21) of the dosing container (20) and into the dosing container in order to expel a portion of the solution from the dosing container (20).

Description

Pre-filled injection device

Technical Field

The present description relates to the technical field of syringes or syringes, and in particular to pre-filled injection devices.

Background

Prefilled syringes or cartridges (e.g., dual chamber syringes or cartridges) have long been known and are now in widespread use. The dual-chamber syringe or cartridge comprises a tubular containment body and two substances (at least one of which is a liquid substance) contained in two initially separate containment chambers defined inside the tubular body.

The two substances (e.g. solid substance in powder form and liquid substance) are intended to be mixed just before administration/injection to a patient. The liquid substance is for example an injectable solvent. To mix the two substances, the two containment chambers are put into communication in order to reconstitute the injectable solution, for example by providing a bypass element between the two chambers in the pre-filled syringe or cartridge.

Currently, pre-filled syringes that allow the administration/injection of very small doses (e.g., doses of about one or ten milliliters in volume) of reconstitution solution are not known. These doses are required, for example, to administer antibiotics topically, e.g., to inject a cephalosporin antibiotic, such as cefuroxime, in the ocular cavity of the patient.

There is a need to manufacture a pre-filled injection device that allows for the injection of very small doses of reconstitution solution in an accurate and safe manner.

disclosure of Invention

A general object of the present description is to make available a pre-filled injection device that allows to meet said need.

This and other objects are achieved by a pre-filled injection device as defined herein in its more general form and in some specific embodiments thereof.

A pre-filled injection device comprising: a tubular containment body extending between a first opening and a second opening, within which are defined a first containment chamber and a second containment chamber hermetically separated from each other; a first solid or liquid substance contained in the first containing chamber; a first plug and a second plug arranged within the tubular containment body so as to define the second containment chamber therein between the first plug and the second plug, and adapted to slide within the tubular containment body; a second liquid substance, housed within said second housing chamber, intended to be mixed within said tubular housing body with said first solid or liquid substance for reconstituting an injectable solution; wherein the pre-filled injection device further comprises a dosing container having an inlet opening and an outlet opening, the inlet opening being in communication with the first receiving chamber such that the first receiving chamber extends between the first plug and the inlet opening of the dosing container; the dosing container is adapted to contain a portion of the injectable solution; the first plug comprises a projecting appendix adapted to pass through the inlet opening of the dosing container and into the dosing container in order to expel the portion of the injectable solution from the dosing container.

Drawings

The invention will be better understood from the following detailed description of embodiments thereof, given by way of non-limiting example with reference to the accompanying drawings, in which:

fig. 1 shows a side view of a first embodiment of a pre-filled injection device, wherein the device is shown in a first operating configuration;

Figure 2 shows a side view of some of the separate components of the injection device of figure 1;

Figure 3 shows a side view of the injection device of figure 1, wherein the device is shown in a second operating configuration;

figure 4 shows a side view of the injection device of figure 1, wherein the device is shown in a third operating configuration;

figure 5 shows a side view of the injection device of figure 1, wherein the device is shown in a fourth operating configuration;

Figure 6 shows a side view of the injection device of figure 1, wherein the device is shown in a fifth operating configuration;

Fig. 7 shows a side view of a second embodiment of the pre-filled injection device, wherein the device is shown in a first operating configuration;

Fig. 8 shows a side view of the injection device of fig. 7, wherein the device is shown in a second operational configuration;

figure 9 shows a perspective view of the components of the injection device of figure 7;

Figure 10 shows a cross-sectional view of the component of figure 9;

figure 11 shows a cross-sectional view of another component of the injection device of figure 7;

Figure 12 shows a side view of the injection device of figure 7, wherein the device is shown in a third operating configuration;

figure 13 shows a side view of the injection device of figure 7, wherein the device is shown in a fourth operating configuration;

figure 14 shows a side view of the injection device of figure 7, wherein the device is shown in a fifth operating configuration;

Figure 15 shows a side view of the injection device of figure 7, wherein the device is shown in a sixth operating configuration;

Figure 16 shows a side view of the injection device of figure 7, wherein the device is shown in a seventh operating configuration; and

Figure 17 shows a side view of the injection device of figure 7, wherein the device is shown in an eighth operating configuration.

in the drawings, the same or similar elements will be denoted by the same reference numerals.

Detailed Description

With reference to fig. 1 to 6, a first embodiment of a pre-filled injection device 1 is shown, which in the particular example shown is a pre-filled dual chamber syringe. In an alternative embodiment, the pre-filled injection device 1 is a pre-filled cartridge. In other embodiments, more than two chambers may be provided in the pre-filled injection device 1. The pre-filled injection device 1 allows the reconstitution of an injectable solution and the injection of very small doses of said solution, for example the injection of an amount of solution smaller than 1 ml and preferably equal or almost equal to 0.1 ml. Preferably, the dose is less than about 1/25 and preferably equal to 1/50 of the reconstituted injection solution in the pre-filled injection device 1.

with reference to fig. 2, the pre-filled injection device 1 comprises a tubular containment body 3 extending between a first opening 4 or front opening and a second opening 5 or rear opening 5. Inside the tubular body 3, in the operating configuration shown in fig. 1 (referred to as "initial configuration"), a first containment chamber 8 and a second containment chamber 9 are defined, hermetically separated from each other. The first accommodation chamber 8 will be referred to as a front chamber, and the second accommodation chamber 9 will be referred to as a rear chamber.

preferably, the pre-filled injection device 1 comprises a closure device 2 fastened to the tubular body 3, for example to the outer lateral wall of the tubular body 3 at one end portion of the first containment chamber 8. According to an alternative embodiment, the closure device 2 is integrally formed with the tubular body 3 and is thus an end portion of the tubular body 3. Preferably, the pre-filled injection device 1 comprises an ergonomic gripping section 12, on the opposite side with respect to the closure device 2, which is fastened to the tubular body 3 or is integral with the tubular body 3.

The tubular body 3 is, for example, in the form of a containing body of a syringe or cartridge suitable for containing the injectable substance, and it is preferably made of a transparent or substantially transparent glass or plastic material. Preferably, the tubular body 3 is made in a single piece.

The pre-filled injection device 1 comprises:

A first solid or liquid substance, contained in the first containment chamber 8;

a first plug 6 and a second plug 7, arranged inside the tubular body 3 so as to define a second housing chamber 9 in the tubular body 3 between them, and adapted to slide inside the tubular body 3 (for example, due to pushing or pulling forces);

a liquid second substance, housed inside the second housing chamber 9, intended to be mixed with the first substance inside the tubular body 3 for reconstituting the injectable solution.

Preferably, the first substance is a highly active substance.

the first substance is for example a powder, a granulated substance, a sterile tablet or a pressed powder. The first substance may be or may contain an API. According to one embodiment, the first substance comprises two different substances, for example in the form of two different tablets, each tablet comprising one of said two different substances.

In the case where the first substance is a solid, the first substance may be a crystalline or lyophilized substance. The form in which the first material is crystalline and not lyophilized is the presently preferred form. In the case where the first substance is a lyophilized powder, it is preferable to obtain said powder by performing a lyophilization process before inserting the first substance into the first containment chamber 8.

the first substance is for example a highly active substance such as a beta-lactam antibiotic, or a cephalosporin antibiotic or a cytotoxic antineoplastic agent or a hormone or a biological agent. The first substance may also be a normally active ingredient, i.e. an ingredient which cannot be defined as being highly active.

The plugs 6, 7 are made of plastic material, for example they are hermetically joined to the inner wall of the tubular body 3 and they can slide inside the tubular body 3 under the action of external thrust or pull forces.

preferably, the second liquid substance is an injectable solvent, such as the solvent WFI (water for injection) or lidocaine solution or water and benzyl alcohol solution or sodium chloride physiological solution, or generally any injectable substance suitable for reconstituting another solid or liquid substance. The second liquid substance may be or may include an API (active pharmaceutical ingredient).

according to one embodiment, the first plug 6 (also referred to as the intermediate plug 6) comprises at least one bypass channel initially in a closed state and adapted to be guided into an open state after the application of an external force, such as a pushing force on the plug. Plugs with bypass channels are generally known to those skilled in the art of prefilled injection devices and therefore they will not be described further.

According to an alternative embodiment, the containment body 3 comprises an inner wall provided with a recess 10 adapted to define the bypass channel. In the initial configuration shown in fig. 1, the recess is arranged between the first plug 6 and the first opening 4.

Preferably, the second plug 7 or the rear plug 7 comprises a fastening element adapted to fasten the plunger 52 to the second plug 7, so that the second plug 7 can slide within the tubular body 3 under the pushing or pulling action of the plunger 52. Said fastening element comprises, for example, an internally threaded blind hole made in the thickness of the second plug 7, into which a complementary threaded end portion of the plunger 52 can be inserted and screwed.

The first plug 6 is separated from the first opening 4 so as to define a first receiving chamber 8 or antechamber 8 between the first plug 6 and the first opening 4.

the pre-filled injection device 1 further comprises a dosing reservoir 20 having an inlet opening 21 and an outlet opening 22. The inlet opening 21 communicates with the first receiving chamber 8 such that the first receiving chamber 8 extends between the first plug 6 and the inlet opening 21 of the dosing container 20. In the particular example shown, the dosing container 20 is defined inside the closing means 2, however in a different embodiment it may be part of the same tubular body 3 and substantially a narrow portion of the first containing chamber 8.

according to one embodiment, the dosing container is made of a transparent or translucent material so that its contents can be seen from the outside, and preferably the dosing container comprises a graduated scale which is also visible from the outside.

According to a preferred embodiment, the pre-filled injection device 1 comprises a needle 24, the inner channel of which is in fluid communication with the outlet opening 22 of the dosing reservoir 20. For example, the needle 24 is fastened to the dosing container 20 on the opposite side with respect to the first containing chamber 8. Preferably, the pre-filled injection device 1 comprises a protective cap 25 for the needle 24. Preferably, the protective cover 25 is a telescopic cover formed by a plurality of axially aligned segments which can be guided from an initial configuration, such as that shown in fig. 1, to an open configuration, such as that shown in fig. 5. According to one possible embodiment, the protective cover 25 has an end portion sealed by a removable and/or pierceable membrane or sheet 26.

starting from the initial configuration of fig. 1, due to the pushing action of the plunger 52 (for example due to the manual operation of the plunger 52), the first 6 and second 7 plugs are adapted to slide in the tubular body 3 until reaching the so-called reconstitution configuration shown in fig. 3, in which, due to the bypass 10, the two containing chambers 8 and 9 are in communication with each other, and the second substance 9 enters the first chamber 8 so as to be mixed together with the first substance. In the reconstitution configuration, shaking the pre-filled injection device 1 (e.g., manual shaking) may facilitate mixing of the two substances.

Starting from the operating configuration of fig. 3, while holding the prefilled injection device 1 in such a way as to orient the container 20 upwards and further pushing the plunger 52, both the plugs 6 and 7 can be moved further forward until they come into contact with each other to expel the air present in the first containment chamber 8 until the operating configuration of fig. 4 is reached, called the "air-expulsion-end" configuration.

Starting from the air-discharge complete configuration of fig. 4, still under the pushing action of the plunger 52, after having suitably moved the protective cap 25 in the open configuration, the first plug 6 can be made to slide (under the pushing action of the second plug 7 which is in turn being pushed by the plunger 52) in order to reduce the volume of the first containing chamber 8 and to discharge a portion of the reconstituted solution (from now on referred to as "first portion") from the tubular body 3 through the outlet opening 22 of the dosing container 20 until reaching the so-called pre-application configuration shown in fig. 5, in which:

the first plug 6 closes the inlet opening of the dosing container 20;

a portion of reconstituted solution (from now on referred to as "second portion") is contained in the first containment chamber 8; and is

The dosing container 20 is filled with a portion of reconstituted solution (from now on referred to as "third portion") as a dose of solution to be administered to the patient.

therefore, it should be noted how the dosing container 20 contains a portion of reconstituted solution. More precisely, the dosing container 20 isolates said portions.

preferably, the third portion is less than 1/25, preferably equal to 1/50 of the reconstituted injectable solution.

According to one embodiment, the volume of the dosing container 20 is about one milliliter or about one tenth milliliter.

The first plug 6 comprises a projecting appendix 16 adapted to pass through the inlet opening 21 of the dosing container 20 and enter therein in order to expel a third portion of the solution from the dosing container 20. This occurs for the application of the third portion of the solution and occurs during this application. Preferably, said projecting appendix 16 has a right-cylindrical shape, more preferably with a circular cross-section.

Preferably, said projecting appendix 16 has a cross-sectional area equal to or slightly smaller than the cross-sectional area of the inlet opening of the dosing container 20, so that it can enter the dosing container 20 in airtight engagement with the inner wall of the dosing container 20 during its sliding movement inside the dosing container.

According to a first embodiment, the pre-filled injection device 1 comprises an opening 23 or vent channel 23 (from now on generically called "vent path") adapted to be passed by the second solution portion for its discharge and to allow the projecting appendix 16 to pass through the inlet opening 21 of the dosing reservoir 20.

In fact, in the absence of said vent path 23, due to the incompressibility of the liquid, the second solution portion will resist the further advancement of the first plug 6, which is required to pass from the operating configuration of fig. 5 to the operating configuration of fig. 6. The latter configuration is referred to as the "end of administration configuration". Preferably, said vent path 23 is provided in the closure device 2. Preferably, said vent path 23 is a path initially closed by, for example:

-a removable plug; or

-a removable or openable or pierceable or rupturable wall; or

-a removable or tearable or pierceable membrane; or

-a valve that opens manually or automatically.

said vent path 23 is configured to open, preferably starting from the configuration of fig. 5, so as to allow the pre-filled injection device 1 to be transformed into the configuration of fig. 6.

Said discharge opening path 23 has an input section facing the inside of the first containing chamber 8 and which is separated from the inlet opening 21 of the dosing container 20 and an output section facing the outside of the first containing chamber 8. Preferably, the injection device 1 comprises a cannula 26 for discharging the second solution portion or an external collecting container of the second solution portion, and wherein said outlet section is connected or connectable to the cannula 26 or the external collecting container.

From what has been described above, it is evident that the quantity of reconstitution solution to be administered in the embodiment of figures 1 to 6, i.e. the dose to be injected, is determined by:

-discharging a first portion of reconstituted solution from the tubular body 3;

-separating the second portion of reconstituted solution in the tubular body 3;

-separating a third portion of reconstituted solution in the dosing container 20;

Wherein the second part is intended to be discharged through the discharge path 23 at the same time as the third part of the reconstituted solution is discharged from the dosing container 20 for administration.

In an alternative embodiment, which will be described hereinafter with reference to fig. 7 to 17, instead of the vent path 23, at least one storage container 32, 26 is provided in the injection device 1, adapted to be transformed from the closed configuration to the open configuration after the first plug 6 exerts a pressure on the second portion of reconstituted solution, so as to be filled by the second portion of reconstituted solution and to allow the projecting appendix 16 to pass through the inlet opening of the dosing container 20 and into the dosing container 20.

Preferably, the total volume of the storage containers 32, 36 is equal to the volume of the dosing container 20.

preferably, the storage containers 32, 36 are ring-shaped containers.

Referring to fig. 9-11, according to one embodiment, the storage containers 32, 36 are initially closed by tearable membranes or membranes 42, 46, and thus are initially unable to receive the reconstitution solution. With reference to fig. 9 to 11, in the particular example shown, the storage container comprises two container portions 42 and 46 defined in the closure device 2 and the first plug 6, respectively. Each of such storage container portions 42, 46 has an annular and/or semi-annular shape and is initially closed by a respective tearable membrane or membrane 42, 46. Preferably, the two container portions 42, 46 are opposite each other and initially, i.e. in the operating configuration of fig. 7, they are located on opposite ends of the first containing chamber 8.

Referring to fig. 7, initially in the operating configuration shown in this figure (referred to as initial configuration) also in this case, inside the tubular body 3 a first containment chamber 8 and a second containment chamber 9 are defined, hermetically separated from each other. In this configuration, the two container portions 42, 46 are sealed.

Referring to fig. 8, starting from the initial configuration of fig. 7, the configuration of fig. 8 (also referred to as the reconstitution configuration in this case) is reached by applying an external pressing force on the plunger 52, as already explained for the embodiments of fig. 1 to 6.

Starting from the reconstitution configuration of fig. 8 and by continuing to exert an external pressing force on the plunger 52, the configuration of fig. 12 is reached, which in this case is also referred to as "air-discharge-end" configuration and is equal/similar to the configuration already explained with reference to fig. 4.

starting from the air-discharge-complete configuration of fig. 12 and by continuing to exert an external pressing force on the plunger 52, the first plug 6 can be made to slide (under the pushing action of the second plug 7, which is in turn being pushed by the plunger 52) in order to reduce the volume of the first containing chamber 8 and cause a portion of the reconstituted solution to be discharged from the tubular body 3 through the outlet opening of the dosing container 20 and therefore through the needle 24, until reaching the so-called pre-application configuration shown in fig. 13, in which:

the first plug 6 closes the inlet opening 21 of the dosing container 20;

a second portion of injectable solution is contained in the first containment chamber 8; and is

the dosing container 20 is filled with a third portion of injectable solution as a dose to be administered to the patient.

Starting from the pre-application configuration shown in fig. 13, by applying further pressure on the plunger 52, the second portion of the incompressible liquid causes the tearable membrane or membranes 42, 46 to rupture or tear and allows the second portion to enter the storage containers 32, 36, as shown in fig. 14 (end-of-application configuration). In the particular example shown, the two storage container portions 32, 36 are opposite each other so as to define a single annular container which, in the particular example shown, surrounds the projecting appendix 16 of the first plug 6. While the tearable membranes or membranes 42, 46 are ruptured or torn, the protruding appendages 16 enter the storage containers 20 and the reconstitution solution contained therein is administered through the needles 24.

According to a particularly advantageous embodiment, it can be envisaged that the two plugs 6, 7 are provided with fastening elements (for example engagement elements) which allow the two plugs 6, 7 to be fastened together once the second plug 7 contacts the first plug 6 and exerts a further thrust on the plunger 52 (in the figures, this occurs when transitioning from the configuration of fig. 8 to the configuration of fig. 12). In the particular example shown, without any limitation set, the fastening element comprises a spherical appendage 71 projecting from the second plug 7 towards the first plug 6 and an opposite mating recess 61 defined inside the first plug 6. As can be appreciated, the forcing of the ball-shaped appendage 71 into the mating recess 61 causes the two plugs 6, 7 to couple so that they are integral with each other.

In the different embodiments described above, which generally refer to the possibility of coupling the two plugs 6 and 7 to each other by exerting an external pulling force on the plunger 52 starting from the configuration of fig. 14, the two plugs 6 and 7 can be moved back until a configuration is reached, for example as shown in fig. 15, in which the projecting appendix 16 is disengaged from the inlet opening 21 of the storage container 20. By rotating the injection device 1 such that the dosing container 20 is oriented downwards, as shown in fig. 16, a second portion of the solution inside the dosing container 20, already stored in the storage containers 36, can be discharged and a second application of the solution is performed (for example in case of unsuccessful first application), then the configuration of fig. 17, referred to as second application end configuration, is reached.

From the above description, it is evident that the amount of reconstitution solution to be administered in the embodiments of fig. 1 to 6 is determined by:

-discharging a first portion of reconstituted solution from the tubular body 3;

-separating the second portion of reconstituted solution in the tubular body 3;

Wherein the second portion is intended to enter the reservoir 32, 36 while the third portion of the reconstituted solution is expelled from the dosage container 20 for administration.

It should also be appreciated that in the described embodiment, after the first application, the dosing container 20 may be reloaded with a second portion and a new application performed.

the embodiments of the invention and the details of the embodiments may be varied widely with respect to what has been described and illustrated by way of non-limiting examples, without thereby departing from the scope of protection defined by the annexed claims.

Claims

1. A pre-filled injection device (1) comprising:

-a tubular containment body (3) extending between a first opening (4) and a second opening (5), inside which a first containment chamber (8) and a second containment chamber (9) are defined, hermetically separated from each other;

-a first solid or liquid substance, contained in said first containment chamber (8);

-a first plug (6) and a second plug (7) arranged inside said tubular containment body (3) so as to define said second containment chamber (9) in said tubular containment body (3) between them and adapted to slide inside said tubular containment body (3);

-a second liquid substance, contained within said second containment chamber (9), intended to be mixed with said first solid or liquid substance within said tubular containment body (3) for reconstituting an injectable solution;

The method is characterized in that:

-the pre-filled injection device (1) further comprises a dosing reservoir (20) having an inlet opening (21) and an outlet opening (22), the inlet opening (21) being in communication with the first receiving chamber (8) such that the first receiving chamber (8) extends between the first plug (6) and the inlet opening (21) of the dosing reservoir (20);

-said dosing container (20) is adapted to contain a portion of said injectable solution;

-said first plug (6) comprises a projecting appendix (16) adapted to pass through said inlet opening (21) of said dosing container (20) and into said dosing container in order to expel said portion of injectable solution from said dosing container (20);

Wherein the pre-filled injection device comprises a vent path (23) adapted to be traversed by a second solution portion for expelling the second solution portion and adapted to allow the projecting appendix (16) to pass through the inlet opening (21) of the dosing container (20).

2. The pre-filled injection device (1) according to claim 1, wherein the vent path (23) has an inlet section facing the inside of the first containment chamber (8) and separated from the inlet opening (21) of the dosing container (20) and has an outlet section facing the outside of the first containment chamber (8).

3. the pre-filled injection device (1) according to claim 2, wherein the pre-filled injection device (1) comprises a cannula (26) for discharging the second solution portion or an outer collection container of the second solution portion, and wherein the outlet section is connected to the cannula (26) or the outer collection container.

4. The pre-filled injection device (1) according to claim 1, wherein the projecting appendix (16) is an appendix having a straight cylindrical shape.

5. The pre-filled injection device (1) according to claim 1, wherein the projecting appendix (16) has a cross-section equal to or slightly smaller than the area of the inlet opening of the dosing container (20) so that it can enter the dosing container (20) by sealing engagement with the inner wall of the dosing container during sliding into the dosing container (20).

6. The pre-filled injection device (1) according to claim 1, wherein the fraction of the injectable solution is smaller than 1/25 of the reconstituted injectable solution.

7. The pre-filled injection device (1) according to claim 6, wherein said fraction of the injectable solution is equal to 1/50 of the reconstituted injectable solution.

8. A pre-filled injection device (1) comprising:

the method is characterized in that:

The pre-filled injection device comprises at least one storage container (32, 36) adapted to be transformed from a closed configuration to an open configuration after the first plug (6) exerts a pressure on the reconstituted second solution portion, so as to be filled by the reconstituted second solution portion and allow the projecting appendix (16) to pass through the inlet opening of the dosing container (20) and into the dosing container (20).

9. The pre-filled injection device (1) according to claim 8, wherein the total volume of the storage containers (32, 36) is equal to the volume of the dosing container (20).

10. the pre-filled injection device (1) according to claim 8, wherein the storage container (32, 36) is an annular container.

11. The pre-filled injection device (1) according to claim 8, wherein the storage container (32, 36) is initially closed by a tearable membrane or membrane (42, 46), whereby the storage container initially cannot receive the reconstituted solution.

12. the pre-filled injection device (1) according to claim 8, wherein the storage container comprises two container portions defined in the closure device (2) and the first plug (6), respectively.

13. The pre-filled injection device (1) according to claim 12, wherein each of said container portions has an annular and/or semi-annular shape and is initially closed by a respective tearable membrane or membrane (42, 46).

14. The pre-filled injection device (1) according to claim 8, wherein the projecting appendix (16) is an appendix having a straight cylindrical shape.

15. The pre-filled injection device (1) according to claim 8, wherein the projecting appendix (16) has a cross-section equal to or slightly smaller than the area of the inlet opening of the dosing container (20), so that it can enter the dosing container (20) by sealing engagement with the inner wall of the dosing container during sliding into the dosing container (20).

16. The pre-filled injection device (1) according to claim 8, wherein the fraction of the injectable solution is smaller than 1/25 of the reconstituted injectable solution.

17. the pre-filled injection device (1) according to claim 16, wherein said fraction of the injectable solution is equal to 1/50 of the reconstituted injectable solution.